title: PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel, and CMF versus a standard-dosed epirubicin-cyclophosphamide followed by paclitaxel with or without darbepoetin alfa in primary breast cancer--outcome on prognosis.
abstract: BACKGROUND
  The objective of this study was to compare the effect of dose-intensified neoadjuvant chemotherapy with that of standard epirubicin plus cyclophosphamide followed by paclitaxel in combination with or without darbepoetin on survival in primary breast cancer.
  
  
  METHODS
  A total of 733 patients received either four cycles of neoadjuvant epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 3 weeks followed by four cycles of paclitaxel 175 mg/m(2) every 3 weeks (EC→T), or three cycles of epirubicin 150 mg/m(2) every 2 weeks followed by three cycles of paclitaxel 225 mg/m(2) every 2 weeks followed by three cycles of combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (E(dd)→T(dd)→CMF). The patients were randomly assigned to receive darbepoetin or none. The primary objective was to demonstrate a superior disease-free survival (DFS) of E(dd)→T(dd)→CMF compared with EC→T.
  
  
  RESULTS
  Estimated 3-year DFS was 75.8% with EC→T versus 78.8% with E(dd)→T(dd)→CMF [hazard ratio (HR) 1.14; P = 0.37] and overall survival (OS) 88.4% versus 91.5% (HR 1.26; P = 0.237). Three-year DFS was 74.3% with darbepoetin versus 80.0% without (HR 1.31; P = 0.061) and OS 88.0% versus 91.8% (HR 1.33; P = 0.139). Patients with a pathologically documented complete response [pathological complete response (pCR)] had a significantly better DFS compared with those without achieving a pCR (estimated 3-year DFS: 89.2% versus 74.9%; HR 2.27; P = 0.001).
  
  
  CONCLUSIONS
  Neoadjuvant dose-intensified chemotherapy compared with standard chemotherapy did not improve DFS, whereas the addition of darbepoetin might have detrimental effects on DFS.
authors.affiliation: Department of Obstetrics and Gynecology, Helios Klinikum Berlin-Buch, Berlin. Electronic address: michael.untch@helios-kliniken.de.
authors.forename: M
authors.initials: M
authors.lastname: Untch
authors.affiliation: German Breast Group, Neu-Isenburg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: von Minckwitz
authors.affiliation: Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, USA.
authors.forename: G E
authors.initials: GE
authors.lastname: Konecny
authors.affiliation: Department of Obstetrics and Gynecology, St Barbara Hospital, Hamm.
authors.forename: U
authors.initials: U
authors.lastname: Conrad
authors.affiliation: Hematologic/Oncologic Practice, Wuppertal.
authors.forename: W
authors.initials: W
authors.lastname: Fett
authors.affiliation: University Women's Hospital of Ulm, Ulm.
authors.forename: C
authors.initials: C
authors.lastname: Kurzeder
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Hannover, Hannover.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Lück
authors.affiliation: University Women's Hospital of Freiburg, Freiburg.
authors.forename: E
authors.initials: E
authors.lastname: Stickeler
authors.affiliation: Klinikum, Kassel.
authors.forename: H
authors.initials: H
authors.lastname: Urbaczyk
authors.affiliation: Krankenhaus Bergisch, Gladbach.
authors.forename: B
authors.initials: B
authors.lastname: Liedtke
authors.affiliation: University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen.
authors.forename: M W
authors.initials: MW
authors.lastname: Beckmann
authors.affiliation: Hematologic/Oncologic Clinic München, Munich.
authors.forename: C
authors.initials: C
authors.lastname: Salat
authors.affiliation: Department of Obstetrics and Gynecology, Technical University of Munich, Munich.
authors.forename: N
authors.initials: N
authors.lastname: Harbeck
authors.affiliation: Department of Obstetrics and Gynecology, University Hospital Hamburg-Eppendorf, Hamburg.
authors.forename: V
authors.initials: V
authors.lastname: Müller
authors.affiliation: University Women's Hospital of Mainz, Mainz.
authors.forename: M
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Department of Obstetrics and Gynecology, Ludwig-Maximilians-University Großhadern, Munich.
authors.forename: S
authors.initials: S
authors.lastname: Hasmüller
authors.affiliation: Department of Obstetrics and Gynecology, Ludwig-Maximilians-University Großhadern, Munich.
authors.forename: M
authors.initials: M
authors.lastname: Lenhard
authors.affiliation: German Breast Group, Neu-Isenburg, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Nekljudova
authors.affiliation: Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Lebeau
authors.affiliation: German Breast Group, Neu-Isenburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Loibl
authors.affiliation: University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen.
authors.forename: P A
authors.initials: PA
authors.lastname: Fasching
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000188:drug therapy; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D000068256:Darbepoetin alfa; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D015251:Epirubicin / Q000008:administration & dosage / Q000009:adverse effects; D004921:Erythropoietin / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D015999:Multivariate Analysis; D020360:Neoadjuvant Therapy; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D010349:Patient Compliance; D011300:Preoperative Care; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D004921:Erythropoietin; D000068256:Darbepoetin alfa; D015251:Epirubicin; D003520:Cyclophosphamide; D017239:Paclitaxel; D005472:Fluorouracil; D008727:Methotrexate